Journal of , published on June 6, 2019 as doi:10.2967/jnumed.119.228130

Advanced Imaging in Cardiac Sarcoidosis

Roberto Ramirez MD, Maria Trivieri MD PhD, Zahi A Fayad PhD, Amir Ahmadi MD, Jagat Narula MD PhD, Edgar Argulian MD

All: Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY

Running Title: Imaging in Cardiac Sarcoidosis

Correspondence: Edgar Argulian, MD MPH Division of Cardiology, Mt Sinai St. Luke's Hospital, Icahn School of Medicine 1111 Amsterdam Avenue, New York, NY 10025 Phone: 212 523 3179 Fax: 212 523 4311 E-mail: [email protected]

Potential conflicts of interest: None

ABSTRACT

Sarcoidosis is a chronic disease of unknown etiology characterized by the presence of non- caseating granulomas. Cardiac involvement in sarcoidosis may lead to adverse outcomes such as advanced block, arrhythmias, cardiomyopathy or death. Cardiac sarcoidosis can occur in patients with established sarcoidosis or it can be the sole manifestation of the disease. Traditional diagnostic techniques including have poor sensitivity for diagnosing cardiac sarcoidosis. The accumulating evidence supports the essential role of advanced modalities such as magnetic resonance imaging and positron emission in diagnosis, risk stratification, and management of patients with cardiac sarcoidosis. The current review highlights important theoretical and practical aspects of using cardiac imaging tools in the evaluation of patients with suspected or established cardiac sarcoidosis.

INTRODUCTION

Sarcoidosis is a multisystem disease that can involve the heart among other organs (1). The prevalence of cardiac sarcoidosis (CS) has not been precisely estimated, but it is likely under- recognized when compared to autopsy series (2). Only a minority of patients with systemic sarcoidosis have clinical manifestations suggestive of cardiac involvement, yet it is important to diagnose because of the high incidence of electrical abnormalities and sudden cardiac death that are potentially preventable (3). Sarcoidosis can additionally present with isolated cardiac involvement without other organs being affected. Although a rare presentation, a recent autopsy study showed up to 40% of patients who died suddenly from CS had no obvious extracardiac manifestations (4). Therefore, cardiac evaluation should be sought in high risk patients, particularly in young and middle-aged patients presenting with myocardial disease, unexplained ventricular tachycardia, and/or high degree atrioventricular block. The diagnosis of CS is hindered by the lack of any reliable biomarker or diagnostic test; shortcomings of commonly used cardiac tests (non-invasive and invasive) such as electrocardiogram, echocardiogram, myocardial perfusion imaging and even include low sensitivity and specificity (5). The ‘gold standard’ criteria used in most studies of CS suffer from significant limitations. The Japanese Ministry of Health and Welfare criteria originally published in 1993 and updated in 2006 have not been extensively validated (6). These criteria require histologic confirmation of cardiac involvement via endomyocardial biopsy or clinical confirmation via a combination of major and minor criteria (7,8). More recently, the Heart Rhythm Society published an expert consensus statement which provides more contemporary criteria for diagnosis of CS that include advanced cardiac imaging techniques. However, these criteria recommend tissue diagnosis of extra-cardiac sarcoidosis (9). Advanced imaging modalities, i.e. cardiac magnetic resonance (CMR) and positron emission tomography (PET) have been shown to detect cardiac involvement with prevalence similar to that seen in autopsy studies, and they offer prognostic value beyond traditional clinical criteria (10-13). Numerous reports have highlighted the potential benefits of advanced imaging modalities in improving the ability to identify and treat patients with CS. In the modern practice, these imaging tools play a fundamental role in early diagnosis, assessment of disease activity, prognostication, and monitoring of therapeutic response.

PATHOLOGY RELEVANT FOR CARDIAC IMAGING

It is important to understand certain histopathologic features of CS as they relate to different imaging modalities. The myocardium is most frequently involved in CS; the and endocardium are less frequently affected, and their involvement typically results from direct extension of myocardial disease. The pathologic description of sarcoidosis includes 3 histological stages: edema, granulomatous infiltration, and fibrosis. Mononuclear, predominantly lymphocytic infiltrate and interstitial edema are seen at early stages. Most characteristic lesions of CS are discrete, compact, non-necrotizing, epithelioid granulomas along with areas of patchy fibrosis (14). At later stages, there is a shift from mononuclear phagocytes and CD4+ cells with T helper type 1 response to T helper type 2 response eliciting anti-inflammatory effects and resulting in tissue scarring and replacement fibrosis (15). Areas of focal myocardial involvement disrupt normal myocardial electrical properties predisposing to ventricular arrhythmias including malignant rhythms and sudden cardiac death. From imaging perspective, identification of inflammation is possible due to avidity of mononuclear inflammatory cells for fluorodeoxyglucose (FDG) and tissue edema as seen on T2 weighted CMR imaging. Areas of fibrosis can be identified by late gadolinium enhancement (LGE) on delayed CMR imaging. The progression of CS has not been well studied, but the natural history of focal myocardial disease can be variable ranging from complete resolution to dense transmural fibrosis. Pathology-proven CS most commonly affects the interventricular septum and inferior wall of left , less commonly anterior wall of left ventricle and right ventricle (16). Involvement of the interventicular septum accounts for high rates of atrioventricular conduction abnormalities observed in these patients. From imaging perspective, thinning of the basal septum has been described in patients with advanced sarcoidosis which can be appreciated on echocardiography. In addition to patchy distribution, lesions of CS have a known predilection to subepicardial and mid-wall myocardium (7,8). This contrasts with which initially affects subendocardial region in a predictable fashion. Since subendocardial myocardium has a disproportionate contribution to left ventricular regional wall motion, identification of myocardial involvement due to coronary artery disease can be done by wall motion analysis using echocardiography or cine CMR. On the other end, significant myocardial disease can be present in the subepicardial and mid-wall regions in CS with preserved wall motion and left ventricular emptying. Heart failure is a less common initial presentation of CS, and it typically signifies an advanced disease. Not surprisingly, modalities relying on wall motion analysis have poor sensitivity for CS. Finally, patchy involvement and the typical subepicardial or midwall distribution of CS lesions markedly decrease the sensitivity of blind endomyocardial biopsy for CS (<25%). Electroanatomic mapping or imaging-guided procedures may increase the sensitivity of endomyocardial biopsy but further validation of these approaches is needed (17). As a result, contemporary diagnosis and management of CS heavily rely on advanced cardiac imaging as an emerging clinical standard.

DIAGNOSIS

Echocardiography

Transthoracic echocardiography is the initial imaging modality in patients with suspected CS. It is a useful test for assessing the overall left ventricular systolic function, left ventricular geometry, areas of myocardial thickening or thinning, diastolic parameters, and right ventricular performance. Commonly described echocardiographic findings include regional wall motion abnormalities, aneurysms, thinning of the basal septum, dilated left ventricle, and impaired right or left ventricular systolic or diastolic function (18). At the same time, echocardiography is an insensitive technique for detection of CS, and a normal transthoracic echocardiography cannot be used to rule out the presence of CS. Echocardiography findings can be quite specific in sarcoidosis patients with cardiac symptoms and/or abnormal ECG findings. An abnormal echocardiogram in these patients is highly suggestive of CS with a positive predictive value up to 92% (19). Basal interventicular septal thinning has been described as a characteristic finding in patients with CS (Fig. 1). In one study, interventicular septal thinning defined as basal interventicular septum ≤4 mm and/or basal interventicular septum/interventicular septum ratio ≤0.6 at the time of CS diagnosis was associated with poor long-term clinical outcomes (20). Due to comorbid lung disease, patients with sarcoidosis may have elevated right heart pressures. Sarcoidosis-related pulmonary is an uncommon complication. In a recent large cohort with biopsy confirmed sarcoidosis, the prevalence of pulmonary hypertension was estimated at 12% (21), and it was associated with increased morbidity and mortality (22). Speckle-tracking echocardiography has been introduced as a new echocardiographic technique to assess regional and global left ventricular strain, and has shown promise in early diagnosis of CS. It is helpful for the detection of early changes in myocardial mechanics before left ventricular systolic dysfunction becomes apparent. Joyce et al evaluated 100 patients with systemic sarcoidosis without known CS or other heart disease. When compared with controls, patients with sarcoidosis had impaired global longitudinal strain, and the strain abnormality was associated with a higher rate of major adverse cardiovascular events (23). These findings suggest the need for larger prospective studies to assess the diagnostic accuracy of this technique in early diagnosis of CS.

Single-Photon Emission Computerized Tomography Imaging

Myocardial perfusion imaging using 201Tl and 99mTc-based single-photon emission computerized tomography (SPECT) can identify focal perfusion defects at rest, with either a fixed or a reverse redistribution pattern with vasodilator stress (24-27). Resting myocardial perfusion defects correspond to microvascular compression or fibrogranulomatous replacement of myocardium. Although these defects may not follow the pattern typical for coronary artery disease, alternative diagnoses, specifically coronary artery disease should be ruled out before attributing abnormalities to CS. When stress testing is performed, these defects may improve on stress imaging (in contrast with coronary artery disease). This finding is referred to as reverse distribution which is believed to be secondary to focal reversible microvascular constriction in coronary arterioles around granulomas, although this phenomenon is not specific to CS (28,29). 201Tl and 99mTc-based SPECT myocardial perfusion imaging can be used with 18F-FDG PET for combined assessment of perfusion and inflammation only if appropriate attenuation correction is available. Most centers prefer to use PET because of greater ease of interpreting two sets of images acquired using the same modality, the robust attenuation correction of PET, and the generally higher spatial resolution of PET as compared to that of SPECT. Gallium has been used to detect active inflammatory disease, but it has been abandoned by most centers in the United States due to poor sensitivity and low spatial resolution.

18F-FDG PET

18F-Fluorodeoxyglucose is a glucose analog that is useful in detecting active CS. The ability of 18F-FDG PET to image inflammation in sarcoidosis is due to an increased uptake of 18F-FDG in macrophage-dense regions. Both glucose and 18F-FDG get phosphorylated in active macrophages; while glucose is further metabolized, 18F-FDG-phosphate remains in macrophages and can be imaged. Inflammation imaging is typically combined with resting perfusion assessment using PET myocardial perfusion imaging (with 13N- Ammonia or 82Rubidium) or SPECT. Perfusion defects may be seen by PET or SPECT in the presence of inflammation due to compression of the microvasculature or fibrosis leading to a mismatch between perfusion and 18F-FDG metabolism. Combining inflammation and perfusion imaging permits assessment of the full spectrum of CS and provides valuable diagnostic and prognostic information. The presence of multiple areas of uptake combined with ‘matched’ perfusion abnormalities makes the diagnosis very likely. At the same time, regional 18F-FDG uptake by itself is not specific to CS. As an example, isolated low-intensity lateral wall 18F-FDG uptake without perfusion abnormalities has a lower probability of being diagnostic. Similarly, high 18F-FDG uptake can be seen in hibernating myocardium due to chronic ischemia in patients with coronary artery disease as well as cardiomyopathies with inflammatory component such as active myocarditis or systemic rheumatologic conditions with cardiac involvement. Diffuse 18F-FDG uptake may be seen in patients with inadequate patient preparation for the test. On the other hand, resting perfusion defects may be present in patients with CS who have no significant inflammatory component. Therefore, the absence of 18F-FDG uptake should be interpreted as a sign of no active myocardial inflammation but cannot rule out the presence of CS (30). Staging systems have been proposed for CS using the combination of inflammation and perfusion radionuclide imaging but these classifications lack histologic or outcome validation (31). PET as a diagnostic modality for CS has few advantages. It can be safely performed in patients with intracardiac devices and advanced renal disease. Another advantage of PET with whole-body imaging is the ability to evaluate extracardiac sarcoidosis. The lungs are the most common site of involvement and the thoracic lymph nodes are frequently affected showing bilateral hilar and mediastinal lymphadenopathy on PET imaging (1). Several studies have attempted to determine the accuracy of cardiac PET for diagnosing CS but the true diagnostic performance is largely unknown. In a meta-analysis by Youssef et al (32) which included 164 patients, the collected data showed a pooled sensitivity of 89% and a pooled specificity of 78% in diagnosing CS. In a more recent meta-analysis of 17 studies, the pooled sensitivity of PET was 84% and a pooled specificity was 83% (33). However, these findings should be interpreted with caution because of the limitations of the ‘gold’ standard itself and the pooling of small studies. The diagnostic performance of 18F-FDG PET relies on the appropriate suppression of physiologic glucose utilization by normal cardiomyocytes. To improve specificity in identifying pathologic glucose uptake, several methods have been proposed (although none has been standardized for CS) including prolonged fasting, dietary manipulation with a high fat/very low carbohydrate diet, intravenous heparin, and often a combination of these approaches (30). These strategies may be ineffective in up to 25% of the patients leading to potentially false-positive or inconclusive results (34). Due to these limitations, several studies have evaluated alternative tracers with higher specificity for inflammatory or proliferating cells and without the inconvenience of complicated dietary or fasting preparations. A study by Norikane et al (35), compared the diagnostic accuracy of 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) and 18F-FDG in patients with newly diagnosed cardiac or extracardiac sarcoidosis. The study showed that 18F- FLT uptake in sarcoid lesions was significantly lower compared to 18F-FDG, although sensitivity and specificity (92% and 100%, respectively) were not significantly different between two tracers. Alternative tracer agents that bind to somatostatin receptors on inflammatory cells in sarcoid granulomas, such as 68Gallium-DOTA-Nal-octreotide (68Ga-DOTANOC), may decrease the proportion of inconclusive studies (36). Gormsen et al (37), compared the diagnostic accuracy and inter-observer variability of 68Ga-DOTANOC with 18F-FDG PET. The study showed that 68Ga-DOTANOC has a higher diagnostic accuracy (100% vs 79%) and a lower inter-observer variability, although the study population was small. Both 18F-FLT and 68Ga- DOTANOC do not require any fasting or dietary restrictions.

CMR

CMR is an important advanced imaging modality to screen or evaluate patients with CS, since it allows detection of myocardial edema, perfusion abnormalities, and scarring. It also allows detailed assessment of biventricular geometry and function. Reportedly, CMR has a high sensitivity and specificity for diagnosis of CS (sensitivity 75-100% and specificity 76-78%) (38,39). In addition, CMR is useful for identifying areas for endomyocardial biopsy and increasing sensitivity of tissue diagnosis. CMR can also potentially evaluate inflammatory component of CS. CMR is able to detect edema and inflammation with the addition of T2 weighted imaging and T2 mapping. Although T2 weighted CMR has been suggested as a potential alternative to 18F-FDG PET in detecting inflammation and monitoring response to therapy, this technique suffers from relatively low signal to noise ratio and needs further clinical validation (40,41). LGE on delayed imaging is used for evaluation of myocardial scarring (Fig. 2). Gadolinium, an extracellular contrast agent demonstrates slow washout from areas of fibrosis and inflammation relative to normal myocardium. Although various patterns of LGE may be seen, sarcoidosis lesions are commonly localized in the septal, basal, and lateral segments of the left ventricle and papillary muscles with relative sparing of the subendocardium (39,42). The LGE distribution and the overall LGE pattern are helpful in recognizing CS, but may also be non- specific. The extent of LGE can be quantified, however, there is currently no consensus regarding direct quantification for CS diagnosis. In addition, CMR imaging is limited in patients with cardiac pacemakers or implantable cardioverter-defibrillator devices, and the use of gadolinium is contraindicated in patients with advanced renal disease.

THERAPEUTIC AND PROGNOSTIC CONSIDERATIONS OF CARDIAC PET AND

CMR

18F-FDG PET

Emerging data supports the role of 18F-FDG PET in prognosticating patients with CS. A higher risk of ventricular arrhythmias and death has been described in patients with 18F-FDG uptake and focal perfusion defects. In one study of 118 patients with no known CAD referred for cardiac PET due to established or suspected CS, those with both myocardial perfusion defects and abnormal 18F-FDG uptake had a 4-fold increase in the annual rate of ventricular tachycardia and death. Although inflammation of the right ventricle was rare, those with focal right ventricular inflammation had a 5-fold higher event rate compared to patients with normal perfusion and metabolism. On the other hand, the presence or absence of active extracardiac sarcoidosis was not associated with adverse events (13). A similar finding was described by Tuominen et al in a retrospective analysis of 137 patients who underwent quantitative assessment by 18F-FDG PET imaging for suspected CS. Pathological right ventricular 18F-FDG uptake was more common in patients with cardiovascular events than those without events (46% vs 6%), and a total cardiac metabolic activity value of more than 900MBq significantly predicted cardiac events (27% vs 4%). Patients with pathological right ventricular uptake had significantly higher total cardiac metabolic activity compared to those without right ventricular uptake. Therefore, the combination of pathological right ventricular uptake and high total cardiac metabolic activity should be considered a significant risk factor in patients with CS (43,44). Cardiac PET is the preferred method for determining response to immunosuppressive therapy. Comparison between serial PET studies can be done by visual and/or quantitative analysis of myocardial 18F-FDG uptake, with the latter being a more precise method to assess treatment response (45,46). In one series, Osborne et al (47) analyzed 23 patients who underwent serial PET examinations during immunosuppressive therapy for CS and found that a reduction in the intensity of standardized uptake value (SUV max) or extent (volume of inflammation above a pre-specified SUV threshold) was associated with improvement in left ventricular ejection fraction, while non-responders to therapy (identified by changes in 18F-FDG uptake) had a significant decrease in left ventricular ejection fraction. It has not been well established whether a change in 18F-FDG uptake is associated with a reduction in event rates. Further research is needed to identify appropriate and clinically meaningful quantitative techniques that can be compared longitudinally and to determine if any other imaging techniques can be used to follow response to therapy.

CMR

Presence of LGE on delayed CMR imaging appears to be a strong prognosticator regarding future cardiac events and death in patients with CS, (39,42) and it should be considered in the clinical decision-making regarding implantable cardioverter-defibrillator implantation (9). In a study by Kouranos et al (19), 321 patients with extracardiac biopsy-proven sarcoidosis were followed over a median of 84 months. LGE was the only independent predictor of the primary combined endpoint of all-cause mortality, sustained ventricular tachycardia episodes or hospitalization for heart failure (HR: 5.68; 95% CI 1.74 to 18.49; p=0.004). CMR independently predicted adverse events (HR: 12.71; 95% confidence interval: 1.48 to 109.35; p = 0.021) in patients with cardiac symptoms and/or an abnormal ECG. Greulich et al followed 155 patients with systemic sarcoidosis over a median of 2.6 years. LGE was present in 39 patients (25.5%). The presence of LGE was the strongest independent risk factor (above left ventricular ejection fraction and end-diastolic volume) with a hazard ratio (HR) of 31.6 for death, aborted cardiac death, or appropriate implantable cardioverter- defibrillator discharge (12). In the PET study by Tuominen et al a subset of patients underwent CMR imaging; no adverse events were reported in patents who had no LGE confirming an excellent negative predictive value of this finding (43). In a recent meta-analysis by Hulten et al, 694 subject who underwent CMR were evaluated. The presence of LGE was associated with higher rates of death or ventricular arrhythmia (relative risk 6.20; 95% confidence interval, 2.47-15.6; P<0.001). In addition, the absence of LGE offered reassurance regarding the risk of ventricular arrhythmia or cardiovascular death (48). In terms of prognosis, LGE appears to be more important than 18F-FDG uptake on PET imaging (49) and can therefore be used in decision making regarding device implantation.

18F-FDG PET vs CMR

Several studies have compared the diagnostic capabilities of 18F-FDG PET and CMR (38,50,51). Interpretation of these studies requires caution for several reasons. First, most of the studies were underpowered to detect significant differences between these techniques. Second, the definition of ‘gold standard’ in diagnosing CS remains elusive. Finally, these modalities detect different pathologic features of CS: inflammation with 18F-FDG PET and largely scarring with LGE CMR. The ability of 18F-FDG PET to characterize inflammation can theoretically result in earlier diagnosis of CS (52). On the other hand, CMR has a higher spatial resolution than PET, and can detect small areas of fibrosis. Although both 18F-FDG PET and CMR have high sensitivity, CMR may have a higher specificity in diagnosis of CS (53). Among patients who are already on steroid therapy, both CMR and PET may have reduced sensitivity but CMR may perform better (38). An important advantage of CMR is a substantially lower number of non-diagnostic scans compared to 18F-FDG PET, which are related to technical difficulties in patient preparation before the study. Additional benefits of CMR relative to 18F-FDG PET include no exposure to ionizing radiation, no need for specialized patient preparation, and the ability to identify alternative cardiomyopathies or infiltrative diseases. In a study by Ju Lee (51), 104 patients with suspected CS were evaluated by both CMR and 18F-FDG PET. LGE was seen in 79 (76%) of the cases, compared to 18F-FDG uptake which was only seen in 31 cases (30%) (p<0.001). 18F-FDG uptake without LGE was uncommon in that study. On the other hand, one small study (38) compared 18F-FDG PET with CMR and found that PET has a numerically higher sensitivity than CMR (88% vs 77%), although this was not statistically significant.

CMR/PET Hybrid Imaging

Although CMR and PET detect different histopathologic features of CS, the complementary role of these tests has not been well defined. Hybrid imaging with combined CMR/PET offers the advantage of an accurate assessment of function and identification of fibrosis by CMR, and assessment of inflammation using 18F-FDG PET. Four patterns have been recognized based on combined imaging results: 1) CMR+PET+, when a LGE pattern is aligned with increase focal 18F-FDG uptake, likely representing active CS (Fig. 3); 2) CMR+PET-, when a LGE pattern is seen by CMR but no activity is detected by 18F-FDG, secondary to inactive CS with myocardial scarring (Fig. 4); 3) CMR-PET-, without LGE or 18F-FDG uptake, likely normal pattern; 4) CMR-PET+, when LGE is negative but there is increased 18F-FDG uptake (either focal, focal- on-diffuse, or diffuse uptake). The last pattern may signify a false-positive study due to failed myocardial suppression and/or physiological uptake by normal myocardium, although in some cases this pattern may also represent an early stage of CS that is not yet visible on LGE. In a study by Vita et al (54), 107 patients with suspected CS were evaluated by both CMR and PET. Overall, 91 patients (85%) were LGE positive, among these 91 patients, 60 patients (66%) had abnormal 18F-FDG uptake suggestive of active inflammation. In patients having both LGE and 18F-FDG uptake the likelihood of CS was higher, and a significantly higher use of immunosuppressive therapies was observed. A study by Dweck et al evaluated 25 patients with the use of hybrid imaging with PET and CMR to detect active sarcoidosis but this study featured simultaneous acquisition. 18F-FDG uptake was quantified using the maximum target-to-normal myocardium ratio (TNMRmax). TNMRmax values were 50% higher in active CS (CMR+PET+) compared to inactive CS or false positive studies (CMR-PET+) (TNMRmax: 1.6 [IQR: 1.3 to 1.9] vs 1.1[IQR: 1.0 to 1.1] respectively [p<0.001]). The study also showed a high sensitivity and specificity for this hybrid approach to detect active CS and a positive correlation between T2 mapping and the TNMR values, although it was not statistically significant. The optimal TNMRmax threshold, using the Youden index, was 1.2 with a sensitivity of 100% and specificity of 94%, with the benefit of lower radiation exposure (8.2 ± 1.5mSv) compared to 18F-FDG PET studies that often require a perfusion tracer for myocardial scar assessment (55). In many patients with suspected CS, the combination of CMR and PET findings provides complementary value for diagnosis, assessment of myocardial function, pattern of injury and disease activity as well as for management of CS (56). Integrating data from both imaging modalities can improve efficiency and reduce patient radiation exposure, with the benefit of providing a unifying approach for diagnosis and management of CS. Although CMR/PET simultaneous acquisition scan is a promising approach, the current availability of scanners capable of this type of hybrid imaging is very limited.

CLINICAL USE OF ADVANCED CARDIAC IMAGING IN CARDIAC SARCOIDOSIS

Advanced imaging modalities have been integrated into clinical care of patients with suspected and established CS based on the emerging data from multiple, mostly single center studies. These studies largely reflect an institutional experience and suffer from a significant heterogeneity in clinical and imaging approaches. Although several documents have attempted to issue clinical recommendations based on the available evidence, these statements acknowledge limitations and challenges faced by the writing committees (9, 30, 31). Advanced cardiac imaging appears to be an essential decision assist tool in the following clinical scenarios in patients with suspected or established CS (Table 1).

1. Diagnostic tool in patients with established extra-cardiac sarcoidosis. Patients with biopsy-proven extracardiac sarcoidosis should be routinely screened for CS (10). The suggested initial screening includes careful history taking, electrocardiogram, transthoracic echocardiogram and possibly 24-hour Holter monitoring (9). Any abnormalities upon the initial screening should be followed by advanced cardiac imaging. CMR is considered the initial test of choice; in patients with contraindications to CMR, 18F-FDG PET combined with myocardial perfusion imaging is an established diagnostic strategy (30,31). Occasionally, 18F-FDG PET is performed in patients with strong suspicion for CS and negative CMR. CMR/PET hybrid imaging is also reasonable in institutions capable of this technique.

2. Diagnostic tool in patients without established extracardiac sarcoidosis. Isolated CS, an underdiagnosed entity represents a great clinical challenge. There is no general consensus on when CS should be clinically suspected in patients without proven extracardiac sarcoidosis and what constitutes the most practical approach to diagnosis. One document suggests evaluation for CS in young patients (<60 years old) with unexplained advanced atrioventricular block (9). Other clinical situations when CS should be suspected include unexplained monomorphic ventricular tachycardia and unexplained cardiomyopathy in a young patient, especially with discrete regional wall motion abnormalities on echocardiography without coronary artery disease. The evaluation for possible CS should include CT scan of the chest looking for evidence of extracardiac sarcoidosis as well as advanced cardiac imaging (CMR or 18F-FDG PET). Suspicious extracardiac lesions identified on chest imaging can be targets for biopsy. Unfortunately, cardiac imaging findings in patients without established extracardiac sarcoidosis can be non-specific. In these cases, electroanatomic mapping or imaging-guided endomyocardial biopsy should be considered (17).

3. Therapeutic response monitoring in patients with established inflammatory CS. Immunosuppressive therapy is commonly used in patients with CS, especially in patients with ventricular dysfunction and electrical abnormalities. Echocardiography and CMR imaging provide overall assessment of the ventricular function but they cannot be used to reliably assess the inflammatory burden. T2 weighted imaging on CMR, while theoretically appealing is not clinically used for therapeutic response monitoring. On the other hand, 18F-FDG PET has gained some observational evidence supporting its clinical utility in therapy initiation and therapeutic response monitoring. Unfortunately, there is limited evidence regarding the optimal monitoring methods (descriptive or qualitative metrics), therapy-specific scan changes and optimal monitoring intervals (30,31).

4. Prognostication in patients with established CS considered for device therapy. Advanced cardiac imaging has an important role in patients with established CS considered for implantable cardioverter-defibrillator for primary prevention of sudden cardiac death. In patients with decreased left ventricular ejection fraction (<35%) inflammation should be identified and treated. There is a strong indication for implantable cardioverter-defibrillator implantation in these patients if the systolic function does not improve with medical therapy and trial of immunosuppression (in patients with inflammation). On the other hand, presence of LGE in patients with mild to moderate left ventricular systolic dysfunction (ejection fraction 35-49%) or right ventricular dysfunction (ejection fraction <40%) may also support implantable cardioverter- defibrillator implantation (9).

The scenarios presented above describe common clinical approaches but also highlight uncertainties and knowledge gaps. It is imperative that future multi-center collaborative studies use systematic and uniform approaches to integration of advanced cardiac imaging into clinical decision making in patients with CS.

CONCLUSIONS

Advanced cardiac imaging techniques have improved the ability to diagnose CS, identify high-risk patients for cardiovascular events, and evaluate response to immunosuppressive therapy. Each imaging modality identifies certain histopathologic features of CS: LGE by delayed CMR imaging is useful for predominantly evaluating fibrosis while PET is best suited for visualizing and quantifying active inflammation. CMR is an attractive initial testing option, and the presence of LGE is the strongest available prognostic marker in patients with CS. Cardiac PET is a good option if CMR is contraindicated, or in occasional cases of strong clinical suspicion with normal CMR findings. It is best suited for patients receiving treatment for CS in determining response to immunosuppressive therapy. Hybrid imaging with CMR/PET is an exciting new imaging approach that incorporates the advantages of both imaging techniques with a single scan which may provide greater certainty in diagnosis of CS. Additional studies are needed to compare the findings of different imaging techniques to assess disease activity and to monitor therapeutic response.

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FIGURE 1. Thinning of the basal septum in a patient with cardiac sarcoidosis as seen on transthoracic echocardiography. The thinning (arrow) is obvious when compared to mid anteroseptum (double arrow)

FIGURE 2. Cardiac magnetic resonance imaging findings in a patient with cardiac sarcoidosis. Four chamber (A) and short axis (B) views demonstrate extensive, patchy areas of late gadolinium enhancement throughout the myocardium.

FIGURE 3. FDG-PET/CMR imaging in patient with cardiac sarcoidosis: a CMR+PET+ patient. Two chamber (A) and short axis (B) views demonstrate a discrete area of late gadolinium enhancement in the inferolateral wall. (C-D). Fused FDG-PET/MR images show increased FDG uptake in the area of CMR abnormality

FIGURE 4. FDG-PET/CMR imaging in patient with cardiac sarcoidosis: a CMR+PET- patient. Short axis views demonstrate (A) avid FDG uptake in mediastinal lymph nodes on fused FDG- PET/MR images and (B) discrete mid-myocardial areas of late gadolinium enhancement in the antero- and inferoseptum without (C) matching increase in FDG uptake.

Tables

TABLE 1. Clinical questions for potential applications of advanced cardiac imaging in patients with suspected or established CS

Clinical Question Clinical Context Diagnosis of CS in patients with established Positive initial screening: history, extracardiac sarcoidosis electrocardiogram, echocardiogram and/or 24-hour Holter monitoring Diagnosis of CS in patients without High of degree of suspicion. Examples established extracardiac sarcoidosis include unexplained electrical abnormalities and unexplained cardiomyopathy Initiation and monitoring of Identification and quantification of immunosuppressive therapy inflammation including longitudinal follow- up Device therapy/implantable cardioverter- Identification of high risk patients for sudden defibrillator cardiac death beyond tradition markers (i.e., left ventricular ejection fraction)